VX-509 (Decernotinib)-Mediated CYP3A Time-Dependent Inhibition: An Aldehyde Oxidase Metabolite as a Perpetrator of Drug-Drug Interactions

Abstract

(R)-2-((2-(1H-pyrrolo [2,3-b]pyridin-3-yl)pyrimidin-4-yl)amino)-2-methyl-N-(2,2,2-trifluoroethyl)butanamide decernotinib) is an oral Janus kinase 3 inhibitor that has been studied in patients with rheumatoid arthritis. Patients with rheumatoid arthritis often receive multiple medications, such as statins and steroids, to manage the signs and symptoms of comorbidities, which increases the chances of drug-drug interactions (DDIs). Mechanism-based inhibition is a subset of time-dependent inhibition (TDI) and occurs when a molecule forms a reactive metabolite which irreversibly binds and inactivates drug-metabolizing enzymes, potentially increasing the systemic load to toxic concentrations. Traditionally, perpetrating compounds are screened using human liver microsomes (HLMs); however, this system may be inadequate when the precipitant is activated by a non-cytochrome P450 (P450)-mediated pathway. Even though studies assessing competitive inhibition and TDI using HLM suggested a low risk for CYP3A4-mediated DDI in the clinic, VX-509 increased the area under the curve of midazolam, atorvastatin, and methyl-prednisolone by approximately 12.0-, 2.7-, and 4.3-fold, respectively. Metabolite identification studies using human liver cytosol indicated that VX-509 is converted to an oxidative metabolite, which is the perpetrator of the DDIs observed in the clinic. As opposed to HLM, hepatocytes contain the full complement of drug-metabolizing enzymes and transporters and can be used to assess TDI arising from non-P450-mediated metabolic pathways. In the current study, we highlight the role of aldehyde oxidase in the formation of the hydroxylmetabolite of VX-509, which is involved in clinically significant TDIbased DDIs and represents an additional example in which a system-dependent prediction of TDI would be evident.

Translational and clinical advances in JAK-STAT biology: The present and future of jakinibs

“…In fact, decernotinib is a selective inhibitor of JAK3 and phase 2 trials have shown efficacy in RA . However, decernotinib also exhibited CYP3A4‐mediated drug–drug interactions thereby affecting metabolism of statins and other drugs . PF‐06651600 is another selective JAK3 inhibitor being studied in RA, alopecia areata, CD, and UC (NCT02974868, NCT02958865, NCT02969044, NCT03395184).…”

“…[162][163][164] However, decernotinib also exhibited CYP3A4-mediated drug-drug interactions thereby affecting metabolism of statins and other drugs. 165 PF-06651600 is another selective JAK3 inhibitor being studied in RA, alopecia areata, CD, and UC 149,166 (NCT02974868, NCT02958865, NCT02969044, NCT03395184). Other JAK3-selective jakinibs are also in development.…”

ecoAO: A Simple System for the Study of Human Aldehyde Oxidases Role in Drug Metabolism

“…These important clearance-contributing processes are often not first-order, yet they have only been described to a limited extent in AO. 20 , 21 , 35 , 45 Finally, inaccurate scaling between in vitro and in vivo clearance data has led to unanticipated rapid first-pass metabolism in several clinical trials, resulting in their failures. 22 , 24 , 27 A plausible explanation for AO clearance underprediction is that AO activity is not constant over the time of the incubation due to enzyme inhibition and/or inactivation.…”

Janus kinase inhibitors in immuno-inflammatory rheumatic diseases: new opportunities and prospects

“…Несмотря на то что «ведущий» цитокин (или цитокины), определяющие эффективность блокады JAK3 при ИВЗ, не известны, данные РПКИ фазы II свидетельствуют об определенных клинических перспективах селективного ингибитора JAK3 (децернотиниб) при РА [91][92][93]. Следует, однако, иметь в виду, что децер-нотиниб, взаимодействуя с CYP3A4, существенно влияет на метаболизм статинов и некоторых других часто применяемых в медицине лекарственных препаратов [94], что может ограничивать его применение у пациентов с ИВЗ с коморбидными заболеваниями. В настоящее время клинические исследования этого препарата приостановлены.…”